**3. Clinical trials on effectiveness of preprandial complementary (= supplementary) insulin boluses in T2D**

Disturbed dynamics of insulin secretion in T2D (**Figure 10**) makes the need of small complementary preprandial boluses of rapid insulin understandable. In the years 1991–2019 we carried out three single centre trials to this topic.

### **3.1 Trial on effectiveness of rapid insulin**

In 1991–1994, a nonrandomized uncontrolled study with 251 T2D assessed the effectiveness of supplementary insulin regimen [40, 41] The complementary insulin therapy using insulin pen MADI started in hospital following the baseline PG profile on day 2. The final ten-point PG profile was performed on day 4. (**Figures 11** and **12**) At a check-up 8–10 weeks later a decrease of HbA1c, BMI and improved lipoprotein-spectrum was found (**Figures 13** and **14**).

We concluded that in T2D better metabolic control can be achieved with complementary insulin therapy than with oral antidiabetic drugs or long-acting insulin 1–2 times daily. Our "surprising" results were based on pathophysiologic concept of Bruns, Berger and Kalfhaus. [7–9] To date, intensive insulin therapy in people with T2D appears to be more accepted in daily routine. [6, 23]

#### **Figure 10.**

*Dynamics of insulin secretion in blood in healthy people (initial postprandial peak is present, insulin concentration returns to baseline within 3 h); in T2D (missing Initial peak, maximum is delayed and hyperinsulinaemia remains over 3 h) [7] (1995).*

*Type 2 Diabetes - From Pathophysiology to Cyber Systems*

the switch back to SMPG. (**Figure 9**).

*Benefits of CGM in individuals on insulin pump [36] (2013).*

**Figure 9.**

*(2005–2009)*

control in T1D in everyday practice settings.

implementation of CGM in perioperative care of T2D.

In the CGM group (but not in the SMPG group) HbA1c significantly dropped within one month and remained reduced as long as the CGM was applied, i.e., until

regular part of treatment in educated persons on insulin pumps.

a suitable alternative to CGM augmented insulin pump therapy.

*2.2.3.2 Multicenter trial on CGM-augmented insulin pump therapy in T1D* 

benefits of CGM-augmented insulin pump therapy for persons with T1D. Community or academic practices in six Central and Eastern European/ Mediterranean countries established a registry of people with T1D starting CGMaugmented insulin pump therapy with the pump PARADIGM® X22 under everyday conditions. We compared HbA1c values before and after 3 months of CGM and assessed relationships between insulin therapy and glycaemia-related variables. Sensor data and HbA1c data were evaluated in 85 of 102 enrolled persons with longstanding T1D, mean age 33.2 ± 16.9 years. Mean HbA1c declined after 3 months of CGM from 59.0 ± 8.9 mmol/mol at baseline to 50.9 ± 11.7 mmol/mol

*2.2.3.3 The trial for CGM benefits in perioperative care (2009–2013)*

The multicenter CGM study (2005–2009) [38] aimed to the assessment of

Hence, CGM-augmented insulin pump therapy appeared to improve glycaemic

Our third CGM study (2009–2013) [39] payed attention to the assessment of

Hence, continuous glucose monitoring with transcutaneous sensors appeared to be an important measure for improving metabolic compensation in people with diabetes. With CGM, the evolution of HbA1c showed metabolic improvement. The PARASEN study demonstrated that continuous self-monitoring should become a

Several years later, the COMISAIR study [37] demonstrated that also a conventional intensive multiple dose insulin regimen (MDI), if supported by CGM, can be

**10**

(P < 0.001).

#### **Figure 11.**

*Ten- point BG profiles (mean ± SE) in insulin-naïve-T2D treated on baseline with oral antidiabetic drugs and/ or diet (upper curve) and then with complementary boluses (4 to 6 U each = 26 U/d) of rapid insulin (lower curve) \*P < 0,05. [40] (1997).*

#### **Figure 12.**

*Ten- point BG profiles (mmol/l, mean ± SE) in T2D treated on baseline with long-acting insulin (1 to 2 boluses/d = 47 U/d) and/or diet and then with complementary boluses (4 to 6 U each = 32 U/d) of rapid insulin (lower curve) \*P < 0,05. [40] (1997).*

#### **Figure 13.**

*Lipoprotein apoLpA1 at baseline and after 8–10 weeks of complementary insulin therapy [41] (1997).*

**13**

**Figure 15.**

*with T2D (\* P < 0,05) [44] (2007).*

*Pathophysiologic Approach to Type 2 Diabetes Management: One Centre Experience 1980–2020*

**3.2 Trial on effectiveness of complementary boluses of rapid insulin analog**

*Lipoprotein apo LpB at baseline and after 8–10 weeks of complementary insulin therapy [41] (1997).*

the end of the 20th century. Their absorption rates prevail over that of regular

The rapid acting insulin anologs (aspart, lispro and glulisin) are available since

The aim of our prospective observational open-label controlled study (2004– 2007) [44] was to compare the effects of insulin analog aspart and human regular insulin resulting from their routine administration in small preprandial boluses

Fifty-seven persons with T2D aged 64.0 ± 1.29 (mean ± SE) years, diabetes duration of 12.4 ± 1.06 years, C-peptide positive, were enrolled into the study. Their treatment with human regular insulin lasted 5.2 ± 0.44 years. Human regular insulin was replaced with insulin analog aspart. Two check-ups in the course of 330 ± 11.1- day sequential period were carried out. The control group consisted of

Following the switch from human regular insulin to insulin analog aspart,

*Impact of insulin aspart (given according the same algorhithms as human insulin) on HbA1c in 57 persons* 

17 persons of equivalent age, duration of diabetes and insulin dosing.

HbA1c concentration in blood decreased **Figure 15**, while plasma glucose

*DOI: http://dx.doi.org/10.5772/intechopen.96237*

human insulin. [42, 43]

**Figure 14.**

according to identical algorithms.

*Pathophysiologic Approach to Type 2 Diabetes Management: One Centre Experience 1980–2020 DOI: http://dx.doi.org/10.5772/intechopen.96237*

#### **Figure 14.**

*Type 2 Diabetes - From Pathophysiology to Cyber Systems*

*Ten- point BG profiles (mmol/l, mean ± SE) in T2D treated on baseline with long-acting insulin (1 to 2 boluses/d = 47 U/d) and/or diet and then with complementary boluses (4 to 6 U each = 32 U/d) of rapid insulin* 

*Ten- point BG profiles (mean ± SE) in insulin-naïve-T2D treated on baseline with oral antidiabetic drugs and/ or diet (upper curve) and then with complementary boluses (4 to 6 U each = 26 U/d) of rapid insulin (lower* 

*Lipoprotein apoLpA1 at baseline and after 8–10 weeks of complementary insulin therapy [41] (1997).*

**12**

**Figure 13.**

**Figure 12.**

**Figure 11.**

*curve) \*P < 0,05. [40] (1997).*

*(lower curve) \*P < 0,05. [40] (1997).*

*Lipoprotein apo LpB at baseline and after 8–10 weeks of complementary insulin therapy [41] (1997).*

#### **3.2 Trial on effectiveness of complementary boluses of rapid insulin analog**

The rapid acting insulin anologs (aspart, lispro and glulisin) are available since the end of the 20th century. Their absorption rates prevail over that of regular human insulin. [42, 43]

The aim of our prospective observational open-label controlled study (2004– 2007) [44] was to compare the effects of insulin analog aspart and human regular insulin resulting from their routine administration in small preprandial boluses according to identical algorithms.

Fifty-seven persons with T2D aged 64.0 ± 1.29 (mean ± SE) years, diabetes duration of 12.4 ± 1.06 years, C-peptide positive, were enrolled into the study. Their treatment with human regular insulin lasted 5.2 ± 0.44 years. Human regular insulin was replaced with insulin analog aspart. Two check-ups in the course of 330 ± 11.1- day sequential period were carried out. The control group consisted of 17 persons of equivalent age, duration of diabetes and insulin dosing.

Following the switch from human regular insulin to insulin analog aspart, HbA1c concentration in blood decreased **Figure 15**, while plasma glucose

#### **Figure 15.**

*Impact of insulin aspart (given according the same algorhithms as human insulin) on HbA1c in 57 persons with T2D (\* P < 0,05) [44] (2007).*

concentrations in 10-point profiles, daily insulin dose, BMI, and frequency of hypo−/hyperglycemic episodes did not change.

No significant influence of insulin aspart on serum concentrations of triacylglycerols, total cholesterol, and LDL-cholesterol was found. Patients' satisfaction was good. No adverse events were recorded. In the control group, no significant changes of baseline HbA1c, insulin dose and BMI were found.

Hence, insulin analog aspart appears to be more effective than human regular insulin in intensive (complementary) treatment in individuals with T2D.

#### **3.3 Trial on effectiveness of Faster (ultrarapid) Insulin ASPart (FIASP)**

The benefits of faster insulin aspart (insulin aspart + nicotinamid) were described and discussed. [45, 46]

Aim of our prospective monocentric uncontrolled Real World Evidence study (2017–2019) [47] was to compare the efficacy of FIASP with the efficacy of previous therapy with insulin aspart in people with T1D and T2D on MDI or on insulin pump.

No adverse events appeared in any group. In T2D groups (N < 24) an unsignificant tendency to reduction of PG, MPG, HbA1c, body mass and total daily dose of insulin in the course of FIASP therapy was shown.

So, only the evidence of noninferiority of FIASP versus insulin aspart was demonstrated. Introduction of improved algorithms together with intensive patients´ education appears necessary to improve the expected outcomes of FIASP therapeutic regimen.
